Abstract
Background
In 2019 a group of University of Pennsylvania (Hoffman et al., J Neurooncol 145: 321–328, 2019) aimed to explore the prognostic impact of expression of epidermal growth factor receptor (EGFR), one of the most common genetic alterations in WT-GBM, in young adults with IDH-WT GBM, suggesting an inferior outcomes in young adults (< 45yo) with newly diagnosed, IDH-WT GBM. At the same time, our group were considering the dimension of this subpopulation treated in our centre, and we performed the same analysis, comparing datas with affected elderly adults.
Methods
We explore the prognostic impact of EGFR expression status in young adults with IDH-WT GBM, and compare this impact with the affected elderly adults. We therefore analyzed clinical characteristics, tumor genetics, and clinical outcomes in a cohort of adults aged 18–45 years with newly diagnosed WT GBM. We selected a total of 146 patients affected by newly diagnosed IDH-WT GBM who underwent surgery, radiation, and chemotherapy in our Institution in the period ranging between January 2014 and December 2016. We focused primarily on the prognostic impact of EGFR expression.
Results
We confirmed through a Bivariate Analysis that the Age of the Patients, the Volume of the lesions, were statistically strongly associated with the survival parameters; The general OS of the cohort presented a breakthrough point between the patients who were respectively younger and older than 45 years, EGFR mutation was per se not associated to a survival reduction in all the cohort patients. When analyzing exclusively the Survival parameters of the patients whose age was under 40, it was possible to outline a non statistically significant trend towards a lesser OS in younger patients harboring an EGFR expression.
Conclusions
Once again the main difference in terms of OS in GBM is shown in a EOR and in Age. To our knowledge, ours is the second study (Hoffman et al., J Neurooncol 145: 321–328, 2019) to evaluate the prognostic impact of EGFR CN gain specifically in young adults with IDH-WT GBM and in the era of modern radiation and Temozolomide, but is the first one to compares this impact with a population of adults over 45, and correlates this date with clinical onset, dimension and localization of disease between this groups. We suggest other centers to evaluate this important finding with a larger number of patients and we are inclined to accept collaborations to increase the power of this study.
Abbreviations
- GBM:
-
Glioblastoma
- IDH-WT GBM:
-
IDH wild-type glioblastoma
- DTI:
-
Diffusion tensor imaging
- DWI:
-
Diffusion weighted imaging
- EGFR:
-
Epidermal growth factor receptor
- EOR:
-
Extent of resection
- FLAIR:
-
Fluid attenuated inversion recovery
- fMRI:
-
Functional magnetic resonance imaging
- GTR:
-
Gross total resection
- HGG:
-
High grade gliomas
- IDH:
-
Isocitrate dehydrogenase
- IoN:
-
Intraoperative neurophysiological monitoring
- IoNT:
-
Intraoperative neuropsicological testing
- LGG:
-
Low grade gliomas
- KPS:
-
Karnofsky performance status
- MPRAGE:
-
Magnetization-prepared rapid gradient-echo
- MRI:
-
Magnetic resonance imaging
- NTR:
-
Near total resection
- STR:
-
Subtotal resection
- ROI:
-
Region of interest
- OS:
-
Overall survival
- PFS:
-
Progression free survival
References
Crocetti E, Trama A, Stiller C, Caldarella A, Soffietti R, Jaal J, Weber DC, Ricardi U, Slowinski J, Brandes A, RARECARE working Group (2012) Epidemiology of glial and non-glial brain tumours in Europe. Eur J Cancer 48:1532–1542
Ohgaki H, Kleihues P (2013) The definition of primary and secondary glioblastoma. Clin Cancer Res 19(4):764–772. https://doi.org/10.1158/1078-0432.CCR-12-3002
Hoffman DI, Abdullah KG, McCoskey M, Binder ZA, O’Rourke DM, Desai AS, Nasrallah MP, Bigdeli A, Morrissette JJD, Brem S, Bagley SJ (2019) Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma. J Neurooncol 145:321–328
Brennan CW, Verhaak RG, McKenna A et al (2013) TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell 155(2):462–477
Ferguson SD, Xiu J, Weathers S-P et al (2016) GBM-associated mutations and altered protein expression are more common in young patients. Oncotarget 7(43):69466–69478
Binder ZA, Thorne AH, Bakas S et al (2018) Epidermal growth factor receptor extracellular domain mutations in glioblastoma present opportunities for clinical imaging and therapeutic devel- opment. Cancer Cell 34(1):163-177.e7
Louis DN et al (2016) The 2016 World Health Organization Classification of tumors of the central nervous system: a summary. Acta Neurpathol 13:803–820
Malakhov N, Lee A, Garay E, Becker DJ (2018) Schreiber 5. Patterns of care and outcomes for glioblastoma in patients with poor performance status. J Clin Neurosci 52:66–70
Yao F, Wang J, Yao J, Hang F, Lei X, Cao Y (2017) Three-dimensional image reconstruction with free open-source OsiriX software in video-assisted thoracoscopic lobectomy and segmentectomy. Int J Surg 39:16–22
Armocida D, Pesce A, Frati A, Miscusi M, Paglia F, Raco A (2019) Pneumoventricle of unknown origin: a personal experience and literature review of a clinical enigma. World Neurosurg 122:661–664
Frati A, Pesce A, Palmieri M, Iasanzaniro M, Familiari P, Angelini A et al (2019) Hypnosis-aided awake surgery for the management of intrinsic brain tumors versus standard awake-asleep-awake protocol: a preliminary, promising experience. World Neurosurg 121:e882–e891
Raco A, Pesce A, Fraschetti F, Frati A, D’Andrea G, Cimatti M, Acqui M (2017) Motor outcomes after surgical resection of lesions involving the motor pathway: a prognostic evaluation scale. World Neurosurg 103:748–756
Frati A, Pesce A, D’Andrea G, Fraschetti F, Salvati M, Cimatti M et al (2018) A purely functional Imaging based approach for transcortical resection of lesion involving the dominant atrium: towards safer, imaging-guided, tailored cortico-leucotomies. J Clin Neurosci 50:252–261
Raco A, Pesce A, Fraschetti F, D’Andrea G, Polli FM, Acqui M, Frati A (2018) Risk of postoperative performance status worsening after resection of lesions involving the motor pathway: a multinomial logistic regression model. J Neurol Surg A 79(06):453–463
Pesce A, Palmieri M, Armocida D, Frati A, Miscusi M, Raco A (2019) Spinal mixopapillary ependymoma: the Sapienza University experience and comprehensive literature review concerning the clinical course of 1602 patients. World Neurosurg 129:245–253
Neilsen BK, Sleightholm R, McComb R, Ramkissoon SH, Ross JS, Corona RJ, Miller VA, Cooke M, Aizenberg MR (2019) Comprehensive genetic alteration profiling in primary and recurrent glioblastoma. J Neurooncol 142(1):111–118
MacLeod RAF, Schneider B, Sivakova I, Nagel S, Dirks WG, Mraz P, Kubikova E, Perzelova A (2019) High level EGFR amplification in a newly established glioblastoma cell line 170-MG-BA. Neoplasma 66(1):109–117
Chistiakov Dimitry A, Chekhonin Ivan V, Chekhonin Vladimir P (2017) The EGFR variant III mutant as a target for immunotherapy of glioblastoma multiforme. Eur J Pharmacol. https://doi.org/10.1016/j.ejphar.2017.05.064
Ceccarelli M, Barthel FP, Malta TM et al (2016) TCGA Research Network. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164(3):550–563
Turner KM, Deshpande V, Beyter D et al (2017) Extrachromosomal onco- gene amplification drives tumour evolution and genetic heteroge-neity. Nature 543(7643):122–125
French PJ, Eoli M, Sepulveda JM, de Heer I, Kros JM, Walenkamp A, Frenel JS, Franceschi E, Clement PM, Weller M, Ansell P, Looman J, Bain E, Morfouace M, Gorlia T, van den Bent M (2019) Defining EGFR amplification status for clinical trial inclusion. Neuro Oncol. 21(10):1263–1272
Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170(5):1445–1453
Villani V, Tanzilli A, Telera SM, Terrenato I, Vidiri A, Fabi A, Zucchella C, Carapella CM, Marucci L, Casini B, Carosi M, Oppido PM, Pace A (2019) Comorbidities in elderly patients with glioblastoma: a field-practice study. Future Oncol 15(8):841–850
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773
Niyazi M, Harter PN, Hattingen E et al (2016) Bevacizumab and radiotherapy for the treatment of glioblastoma: brothers in arms or unholy alliance? Oncotarget 7(3):2313–2328
Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6(3):217–223
Waitkus MS, Diplas BH, Yan H (2016) Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol 18(1):16–26
Sanson M, Marie Y, Paris S et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27(25):4150–4154
Zhang R, Shi Z, Chen H et al (2016) Biomarker-based prognostic stratification of young adult glioblastoma. Oncotarget 7(4):5030–5041
Eskilsson E, Røsland GV, Solecki G, Wang Q, Harter PN, Graziani G, Verhaak RGW, Winkler F, Bjerkvig R, Miletic H (2018) EGFR heterogeneity and implications for therapeutic intervention in glioblastoma. Neuro Oncol 20(6):743–752
Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:166–193
Bilello M, Akbari H, Da X, Pisapia JM, Mohan S, Wolf RL, O’Rourke DM, Martinez-Lage M, Davatzikos C (2016) Population-based MRI atlases of spatial distribution are specific to patient and tumor characteristics in glioblastoma. Neuroimage Clin 12:34–40
Curran WJ, Scott CB, Horton J et al (1993) Recursive partition- ing analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85(9):704–710
Intellectual property
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
Funding
This study was no funded by any association.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. The authors confirm their adherence to ethical standards and have NO financial disclosures that would be a potential conflict of interest with this publication.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.
Research involving with animal and human rights
This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study. The patient has consented to the submission of this review article to the journal.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Armocida, D., Pesce, A., Frati, A. et al. EGFR amplification is a real independent prognostic impact factor between young adults and adults over 45yo with wild-type glioblastoma?. J Neurooncol 146, 275–284 (2020). https://doi.org/10.1007/s11060-019-03364-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-019-03364-z